AU682562B2

AU682562B2 - 3-acylaminobenzodiazepines

Info

Publication number: AU682562B2
Application number: AU12597/95A
Authority: AU
Inventors: John J. Baldwin; David A. Claremon; Jason M. Elliott; Nigel Liverton; David C. Remy; Harold G. Selnick
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1993-11-22
Filing date: 1994-11-21
Publication date: 1997-10-09
Anticipated expiration: 2014-11-21
Also published as: EP0730584A4; US5428157A; AU1259795A; JPH09500395A; WO1995014676A1; EP0730584A1; CA2175217A1

Description

WO 95/14676 PCT/US94113544 -1- TITLE OF THE INVENTION 3-ACYLAMINOBENZODIAZEPINES SUMMARY OF THE INVENTION This invention is concerned with novel compounds represented by structural formula I.

R N H

R

2 ,N R or a pharmaceutically acceptable salt thereof, which are useful as antiarrhythmic agents. The invention is also concerned with pharmaceutical formulations comprising one of the novel compounds as an active ingredient.

The invention is also concerned with a method of treating arrhythmia by the administration of one of the novel compounds or formulation thereof to a patient in need of such treatment.

BACKGROUND OF THE INVENTION Arrhythmias often occur as complications to cardiac diseases such as myocardial infarction and heart failure. In a serious case, arrhythmias give rise to a ventricular fibrillation and can cause sudden death.

Though various antiarrythmic agents are now available on the market, those, having both satisfactory effects and high safety, have not been obtained. For example, antiarrythmic agents of Class I according to the classification of Vaughan-Williams which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (Vmax) are inadequate for preventing ventricular

I

WO 95/14676 PCT/US94/13544 -2fibrillation. In addition, they have problems regarding safety, namely, they cause a depression of the myocardial contractility and have a tendency to induce arrythmias due to an inhibition of the impulse conduction. Beta-adrenoceptor blockers and calcium antagonists which belong to Class II and IV respectively, have a defect that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the antiarrhythmic agents of Class I.

Antiarrythmic agents of Class II are drugs which cause a selective prolongation of the duration of the action potential without a significant depression of the Vmax. Drugs in this class are limited.

Examples such as sotalol and amiodarone have been shown to possess Class III properties. Sotalol also possesses Class II effects which may cause cardiac depression and be contraindicated in certain susceptible patients. Also, amiodarone is severely limited by side effects. Drugs of this class are expected to be effective in preventing ventricular fibrillations. Pure Class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to the inhibition of the action potential conduction as seen with Class I antiarrbythmic agents.

DETAILED DESCRIPTION OF THE INVENTION The novel compounds of this invention have structural formula I:

R

4 IN 0

R

5 N X-R1 IM W-

R

2

R

3 WO 95/14676 PCT/US94/13544 -3or a pharmaceutically acceptable salt thereof wherein: X is C1-4 alkylene, either straight or branched chain;

R

1 is 1) phenyl either unsubstituted or substituted with one or two substituents selected from chloro, trifluoromethyl, bromo, fluoro, C1-3 alkoxy, nitro or iodo; 2) naphthyl, or 3) C5-7 cycloalkyl,

R

2 and R 3 are independently 1) C1-3 alkyl, either straight or branched chain, and either unsubstituted or substituted with phenyl, or 2) C3-7 cycloalkyl; or

R

2 and R 3 taken together represent a C4-7 methylene chain to form with the nitrogen to which they are attached a 5-8 membered azacycle;

R

4 is 1) C1-4 alkyl, 2) phenyl or 3) benzyl; and R5 is 1) hydrogen or 2) C1-3 alkyl.

The pharmaceutically acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quartemary ammonium salts of the compounds of Formula I formed, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glucolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

i I II I WO 95/14676 PCT/US94/13544 -4- The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional chemical methods.

Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.

One embodiment of the novel compounds of this invention is that in which R 2 and R 3 are joined together to form a 5-8-membered heterocycle.

Representative of the compounds within this embodiment are those depicted in Table I.

TABLE I

NX

R

2 ,N R 3 X R1 R-R 3

RA

-CH2- 1-naphthyl -(CH2)5- n-propyl -(CH2)2- 2,4-diCIPh -(CH2)6- methyl -(CH2)2- 4-CF3Ph -(CH2)6- methyl -(CH2)3- cyclohexyl -(CH2)6- methyl -(CH2)4- Ph -(CH2)6- methyl -CH2- 1-naphthyl -(CH2)6- n-propyl -(CH2)3- Ph -(CH2)6- methyl -(CH2)2- cyclohexyl -(CH2)6- methyl -CH2- cyclohexyl -(CH2)6- methyl WO 95/14676 WO 9514676PCT/US94/13544 A second embodiment of the novel compounds of this invention is that wherein R 2 and R 3 are independently C1-3 alkyl or C3-7 cycloalkyl.

Representative of this embodiment are the compounds depicted in Table III.

IN 0 'N N H

N\

CH

3 X R! R -(CH2)2- 4-CF3Ph -C113 -(CH2)3- cyclohexyl -Cf3 -(CH2)2- 2,4-diClPh -C113 -(CH2)2- 2,4-diCiPh n-propyl -(CH2)2- cyclohexyl n-propyl -CH2- cyclohexyl n-propyl -(CH2)2- Ph -CH3 -CH2- cyclohexyl -CH3 -(CH2)3- Ph -CL{3 -(CH2)2- cyclohexyl -CH3 A third embodiment of the novel compounds of this invention is that wherein R 2 and R 3 are independently C1-3 alkyl, or C1-3 alkyl substituted with phenyl.

Specific compounds within this embodiment are those depicted in Table III.

I

WO 95/14676 PCTIUS94/13544 -6- 0 4 110 TABL HI X RI R2 R-2 RA -(CH2)2- 2,4-diCiPh -CZHS -C2U5 -CH3 -(CH2)2- 2,4-diCiPh -CH3 -CH3 benzyl -(CH2)2- cyclohexyl -CH3 -CH3 benzyl -(CH2)2- 2,4-diCiPh -CH3 -CH3 -Ph -CH2- cyclohexyl -CH3 -CH3 -Ph -(CH2)2- 2,4-diCiPh -CH3 benzyl -CH3 -(CH2)2- cyclohexyl -CH3 -CH3 i-propyl -(CH2)2- cyclohexyl -C21{5 -C2115 -CH3 -(CH2)4- Ph -C2J15 -C2H5 -CH3 -(CH2)2- cyclohexyl -CH3 -CH3 -CH3 -CH2- cyclohexyl -C2H-5 -C2H5 -CH3 -CH2- cyclohexyl -CH3 -CH3 n-C3H7 -(CH2)2- 2,4-diClPh -CH3 -CH3 i-propyl -(CH2)2- cyclohexyl -CH3 -CH3 Ph A novel process for preparing the compounds of this invention is schematically exemplified below in Step Steps (a) through show how the penultimate intermediate can be synthesized and these steps are well known in the art and/or described in the Examples that follow.

WO 95/14676 WO 9514676PCTIUS94/13544 -7- N yO0 0 0

H

2

NCH

2

COOH

EtAN H 2 0 (a)

I

1) PC1 2) R 2

R

3

NH

KOtBu,

ONO

IN

N

R R3 Toluene

(C)

EtNCO Et 3 N, THF (d)

R

2 -1 R

R

2 7

~R

3 WO 95/14676 PCTIUS94/13544 -8- 0 R 4 COOH (f) Hp NH 2 EDC, Et 3 N, DMF MeOH N N N N

N

R2 R 3

N

I

OH

R

1

N'

-N'V

N R4 R2 R 3 In the novel process, the 3-amino compound produced in Step of the synthetic scheme is dissolved in a polar organic solvent such as DMF. The resulting solution is then treated with a carboxylic acid such as phenylpropionic acid depending on the nature of the 3amide that is desired followed by treatment with 1-hydroxybenzotriazole hydrate, triethylamine and 1-(3-dimethyl-aminopropyl)-3ethylcarbodiimide. When the reaction is complete after about 14-24 hours at about 15-25 0 C, conveniently at room temperature, it is poured into water and the product isolated by solvent extraction, evaporation and crystallization.

The novel compounds of the present invention, have the pharmacological properties required for antiarrhythmic agents of Class Il, namely the prolongation of the myocardial action potential in vitro, without a significant depression of the Vmax, and the prolongation of QTc-interval in anesthetized dogs.

WO 95/14076 PCT/US94/13544 -9- These compounds are effective in treating and preventing all types of arrhythmias including ventricular and atrial (supraventricular) arrhythmias. The compounds of the present invention are especially useful to control reentrant arrhythmias and prevent sudden death due to the ventricular fibrillation. These compounds are also effective in treating and preventing impaired cardiac pump functions.

In the novel method of this invention of treating arrhythmia, one of the compounds or pharmaceutically acceptable salt thereof, is administered in an amount ranging from about 0.0001 to about 20 mg per kg or body weight per day, preferably from about 0.001 to about 10 mg per kg of body weight per day in a single dose or in 2 to 4 divided doses.

These compounds can be administered as the sole active ingredient or in combination with other antiarrhythmic agents or other cardiovascular agents.

These compounds, or pharmaceutically acceptable salts thereof, in the described dosages, are administered orally, intraperitoneally, subcutaneously, intramuscularly, transdemially, sublingually or intravenously. They are preferably administered intravenously or orally, for example in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, or the like prepared by art recognized procedures. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.

The activity of the compounds described herein as antiarrhythmic agents is measured by their ability to block the IKs and IKr as determined by the following test protocol.

Outward potassium currents are measured in single guinea pig ventricular myocytes using a whole-cell voltage clamp technique described in detail elsewhere (Sanguinetti and Jurkiewicz, 1990, two components of cardiac delayed actifier K+ current: differential sensitivity to block by Class Ifl antiarrhythmic agents. J. Gen Physiol.

96: 195-215). Myocytes are isolated by enzymatic (collagenase and

L-,

WO 95/14676 PCT/US94/13544 protease) digestion of Langandorf perfused hearts. Single cells are then voltage clamped using 1 mm square-bore pipettes filled with 0.5 M Kgluconate, 25 mM KC1, 5 mM K(2)ATP. Cells are bathed in a solution containing, in mN: 132 NaCI, 4KC1, 1.2 MgC![2], 10 HEPES, 10, glucose: pH 7.2, temp. 35 0

C.

Each cell is maintained at a holding potential of -50 mV.

Test depolarizations are applied as voltage ramps from -85 to -50 mV, and steps to -10 mV (0.5 s) and +50 mV (1.0 I[KI] is measured as peak outward current during the voltage ramp. I[Kr] is measured as tail currents upon repolarization from -10 mV to -50 mV. I[KS] is measured as time-dependent current during the pulse to +50 mV.

Currents are measured during control, then after exposure to drug at two different concentrations.

Employing this test the compounds described herein have an IC50 of less then 1000 nM as IKs and/or IKr blockers.

EXAMPLE 1 (±)-N-[2,3-dihydro-l-methyl-2-oxo-5-(N-cyclohexyl-N-methylamino)- 1H-1.4-benzodiazepin-3-yll-3-phenylpropanamide Step A: Me Me 0

N

Si

NCH

CH3 A solution of PCl5 (6.6 g, 32 mmol) in 250 mL dichloromethane was added to a stirred solution of 1-methyl-1,4-benzodiaz- WO 95/14676 PCT/US94/13544 11 (5.0 g, 26 mmol) in 150 mL of dichloromethane. The solution was stirred at room temperature for 3 hours before evaporation of volatiles. The resulting foam was dissolved in 200 mL dichloromethane, the solution cooled to 0 C and a solution of N-methylcyclohexylamine (11.8 mL, 91 mmol) in 50 mL of dichloromethane added over 5 minutes. The reaction mixture was allowed to warm to room temperature, and partitioned. The organic phase was washed with brine, dried (MgSO4) and solvent evaporated to give the product as a foam. Yield 6.9 g.

NMR (300 MHz, CDCl3) 8: 7.60 1H), 7.47 7.52 2H), 7.33 (m, 1H), 4.0 (1/2AB, J 12.2 Hz, 1H), 3.47 (1/2AB, J 12.2 Hz, 1H), 3.35 3H), 3.3 1H), 2.78 3H), 1-0-2.0 Step B: CH

CH

3 0

N

NO NHEt CH- N CH -N A solution of 2,3-dihydro-l-methyl-2-oxo-5-(Ncyclohexyl-N-methylaino)-lH-1,4-benzodiazepine (770 mg, 2.7 mmol) in 10 mL toluene was added to a stirred and cooled suspension of potassium t-butoxide (750 mg, 6.7 mmol) in 25 mL of toluene. After stirring at -30 0 C for 30 minutes, isoamyl nitrite (540 tL, 4.0 mmol) was added and the reaction mixture stirred for 3 hours at -20°C. The mixture was then poured into 10% citric acid solution/ethyl acetate, stirred for 10 minutes, the pH adjusted to 7 with saturated potassium carbonate solution and the phases separated. The organic phase was washed with brine, the organic phase dried (MgSO4) ao~l* WO 95/14676 PCT/US94/13544 -12and the solvent evaporated to give a foam. This was dissolved in 15 mL THF and ethyl isocyanate (395 gL, 5 mmol) added followed by triethylamine (700 gL, 5 mmol). The reaction mixture was heated to 0 C for 2 hours, cooled to room temperature, the volatiles evaporated and the residue purified by flash column chromatography (silica, ethyl acetate/hexane) to afford 720 mg of product as a foam.

NMR (300 MHz, CD30D) 5: 7-7.6 5H), 3.5 1H), 3.42 3H), 2.7-3.3 5H), 1.1-2 10H), 1.05 J 7 Hz, 3H).

Step C: CH N A solution of the oxime carbamate (355 mg, 1.85 mmol) in mL methanol was hydrogenated at 50 psi over 300 mg of palladium/ charcoal for 3 hours. The mixture was filtered through ceilte and the filtrate evaporated to give the crude amine. This was dissolved in 5 ml DMF and phenylpropionic acid (300 mg, 2 mmol), 1hydroxybenzotriazole hydrate (305 mg, 2 mmol), triethylamine (250 WO 95/14676 WO 954676PTIUS94/13544 13 [tL, 1.8 nimol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (380 mg, 2 mmol) added. The reaction mixture was stirred at room temperature for 18 hours, poured into water and extracted with ethyl acetate. The organic phase was washed with sodium bicarbonate solution and brine, dried (MgSO4) and solvent evaporated to give a solid, recrystallized from ethyl acetate/hexane to afford Dihydro-1-methyl-2-oxo-5-(N-cyclohexyl-N-methylamino)-IH- 1,4benzo-diazepin-3-yl]-3-phenylpropanamide.

m.p. 167-168'C.

Anal. Calcd. for C26H32N402 .0.75 cyclohexane: C, 73.9; H, 8.34; N, 11.3.

Found: C, 73.75; H, 8.36; N, 10.79%.

NMR (300 MLz, DMSO) 5: 8.8 J 7.5 Hz, 1H), 7.3-7.65 (mn, 9H), 4.95 J 7Hz,1H), 3.57 (1I2AB, J 13 Hz,1H), 3.48 (1/2AB, J 13 Hz, 1H), 3.1-3.4 (in, 1H), 3.27 3H), 2.65 3H1), 0.9-1.9 (in, 10H1).

By substituting the appropriate acid for phenyipropionic acid, and employing the procedures substantially as described in Example 1 the following compounds were pre-pared.

EXAMPLE 2 -Dihydro-l1-methyl-2-oxo-5-(N-cyclohexyl-N-methylamino)- 1 H-i .4-benzo-diazein-3-yllI-2-cvclohexvlacetamide in.p. 158-159'C.

Anal. Calcd. for C251136N402 0.85 cyclohexane: C, 72.86; H, 9.39; N, 11.29.

Found: C, 72.46; H, 9.4; N, 10.9%.

WO 95/14676 WO 954676PIUS94/13544 14 NMR (300 MfHz, DMSO) 8: 8.44 J 7.8 Hz, 1H), 7.5-7.63 (in, 2H), 7.46 (dd, J 7.8, 1.2 Hz, 1H), 7.32 (in, 1H), 4.95 J =8 Hz, 1H), 3.15-3.45 (mn, 1H), 3.26 3H), 2.64 3H), 1.95-2.1 (in, 2H), 0.8-1.9 (mn, 21H).

EXAMPLE 3 N-[2,3 -Dihydro-1 -methyl-2-oxo-5-(N-cyclohexyl-N-inethylaniino)- 1H- 14-benzo-diazepin-3 -vii-4-p2henylbutanamide m.p. 140-141*C.

Anal. Calcd. for C27H34N402 0.7 Water: C, 70.62; H, 7.77; N, 12.2.

Found: C, 70.58; H, 7.54; N, 12.11%.

NMR (300 MIHz, DMSO) 8: 8.52 J 8.1 Hz, 1H), 7.1-7.6 (rn, 9H), 4.97 J 9.1 Hz, 111), 3.1-3.45 (mn, 1H), 3.26 3H), 2.64 3H), 2.52 (mn, 2H), 2.10-2.30 (ra, 2H), 0.9-1.9 (in, 1211).

EXAMPLE 4 (±)-N-[2,3-Dihydro-1 1 H-i .4-benzo-diazepin-3 -yll -3 -cyclohexylpropanarnide in.p. 170-171'C.

Anal. Calcd. for C26H3&N402 0.55 EtOAc 0.5 cyclohexane: C, 70.81; H, 9.22; N, 10.59.

Found: C, 70.88; H, 9.2; N, 10.55%.

NMR (300 Mz, DMSO) 8: 8.46 J =8.1 Hz, 1H), 7.28-7.65(in, 4H), 4.95 J 8.1 Hz, 1H), 3.1-3.4 (mn, 1H), 3.26 3H), 2.64 (s, 3H), 2.17 J 7.1 Hz, 2H), 0.7-1.9 (mn, 23H).

WO 95/14676 PTU9134 PCT/US94113544 15 EXAMPLE (±)-N-[2,3-Dihydro- 1-methyl-2-oxo-5-(N-cyclohexyl-N-methylamrino)- 1 H-i .4-benzo-diazgpin-3-yl] -3-(4-trifluoromethyl)phenvlpropanamide m.p. 221-223'C.

Anal. Calcd. for C27H31F3N402: C, 64.79; H, 6.24; N, 11.19.

Found: C, 64.73; H, 6.18; N, 11.07%.

NM (300 MfHz, DMSO) 8: 8.63 J 8.1 Hz, 1H), 7.25-7.65 (in, 8H), 4.96 J 8 Hz, 1H), 3.15-3.45 (in, 1H), 3.26 3H), 2.84 J= Hz, 2H), 2.63 3H), 2.53 J 7.5 Hz, 2H1), 0.9-1.9 (mn, 10H1).

EXAMPLE 6 (±)-N-[2,3-Dihydro-1 I-i .4-benzo-diazepin-3 -yll -4-cyclohexylbutanamide in.p. 143 -145'C.

Anal. Calcd. for C27H40N402, 1.0 C, 68.9; H, 9; N, 11.9.

Found: C, 68.85; H, 8.67; N, 12.01%.

NMR (300 MFz, DMSO) 8: 8.46 J 8.1 Hz, 1H), 7.25-7.65 (in, 4H), 4.95 J 8 Hz, 1H1), 3.15-3.4 (mn, 1H1), 3.26 3H), 21.64 (s, 311), 2.13 J 7.5 Hz, 2H), 0.7-1.9 (in, EXAMPLE 7 -Dihydro-l1-methyl-2-oxo-5-(N-cyclohexyl-N-methylamino)- 1H-i 4-benzo-diazepin-3 -vii-3 -(2.4-dichlorop~henvl)p2ropanamide in.p. 184-185'C.

WO 95/14676 WO 95/4676 CTJUS94/13S44 16 Anal. Calcd. for C26H30Cl2N402, 0.8 C, 60.53;,H, 6.17; 10.86.

Found: C, 60.5; H, 5.61; N, 10.82%.

NMiR (300 MIHz, DMSO) 8: 8.66 J 8.1 Hz, 111), 7.2-7.65 (in, 711), 4.96 J 8.1 Hz, 1H1), 3.15 -3.4 (in, 111), 3.26 3H1), 2.83 J 7.2 Hz, 2H), 2.64 311), 2.5 2H), 0.9-1.9 (in, 10H1).

By using diethylainine in place of N-methylcyclohexylamine and the appropriate acid, the following compounds were prepared by the processes described in Example 1.

EXAMPLE 8 (±)-N-[2,3-Dihydro- 1-methyl-2-oxo-5-(NN-diethylamino)- IH- 1,4benzodiazep~in-3-yl] -3 -(2,4-dichloroplhenyl)prop~anamide m.p. 177-178'C.

Anal. Calcd. for C23H26Cl2N4O2: C, 59.87; H, 5.68; N, 12.14.

Found: C, 60.2; H, 5.63; N, 11.91%.

NMR (300 MHz, DMSO) 8: 8.64 J 8.1 Hz, 111), 7.2-7.6 (in, 711), 4.97 J 8.1 Hz, 111), 3.25 -3.4 (in, 211), 3.27 311), 2.9-3.1 (in, 2H), 2.83 J 7.3 Hz, 2H1), 2.5 211), 0.98 J 6.9 Hz, 611).

EXAMPLE 9 (±)-N-[2,3-Dihydro-l1-inethyl-2-oxo-5-(N,N-diethylamino)-l11-1,4benzodiazep2in-3-yl] in.p. 134-135 0

C.

Anal. Calcd. for C25H32N4O2, 0.25 1120: WO 95/14676 WO 9514676PCTIUJS94/13544 17 C, 70.64; H, 7.71; N, 13.18.

Found: C, 70.7; H, 7.94; N, 13.16%.

NMR (300 Mfiz, DMSO) 8: 8.48 J 8.1 Hz, 1H), 7.1-7.6 (in, 9H), 4.97 J 8.1 Hz, 1H), 3.25-3.4 (in, 211), 3.27 3H), 2.95-3.1 (in, 211), 2.53 J 7.1 Hz, 211), 2.20 J 7.1 Hz, 211), 1.4-1.6 (in, 411), 0.97 J 7.1 Hz, 6H).

EXAMPLE benzodiazepin-3-yll -2-cyclohexylacetainide m.p. 192-193'C.

Anal. Calcd. for C221132N402, 0.9 C, 65.93; H, 8.5; N, 13.98.

Found: C, 65.91; H, 7.9; N, 14.05%.

NMR (300 MHz, DMSO) 8: 8.43 J 8.1 Hz, 111), 7.2-7.65 (mn, 4H), 4.96 J 8.1 Hz, 1H), 3.2-3.3 (in, 2H), 3.27 3H), 2.9-3.1 (mn, 2H), 1.95-2.1 (in, 211), 0.8-1.7 (in, 1711).

EXAMPLE 11 -Dihydro-l1-inethyl-2-oxo-5-(N,N-diethylainino)-1H- 1,4benzodiazepin-3 -vi]-3-cyclohexylprop~anamide m.p. 209-210'C.

Anal. Calcd. for C23H34N402: C, 69.31; H, 8.6; N, 14.06.

Found: C, 69.38; H, 8.69; N, 13.69%.

I

WO 95114676 PTU9134 PCTIUS94/13544 18 NMR (300 MfH, DMSO) 8: 8.45 J 8.1 Hz, 1H1), 7.2-7.65 (in, 4H1), 4.96 J =8.1 Hz, 1H), 3.2-3.4 3.27 3H), 2.9-3.1 (in, 211), 2.17 J =7.3 Hz, 211), 0.7-1.7 (i,1911).

By using hexahydroazepine in place of N-methylcyclohexylamine, and the appropriate acid the following compounds were prepared using the processes substantially as described in Example 1.

EXAMPLE 12 N-12,3-Dihydro-1 -methyl-2-oxo-5-(hexahydroazepin- 1-yl)-1H-1 ,4benzodiazepin-3 -vl]-4-phenylbutanamide m.p. 182-183TC.

Anal. Calcd. for C26H32N402 C, 72.19; H, 7.46; N, 12.95.

Found: C, 71.79; H, 7.36; N, 12.57%.

NUR (300 MHz, CD3OD) 8: 1.20-1.98 (in, 1011), 2.27 (in, 211), 2.62 (mn, 211), 3.41 (in, 4H), 4.94 311), 5.09 111), 7.10-7.62 (in, 911).

EXAMPLE 13 N-[2,3-Dihydro-l1-inethyl-2-oxo-5-(hexahydroazepin- 1-yl)-1H-1 ,4benzodiazepiin-3-vll-2-cyclohexyl acetainide m.p. 205-207TC.

Anal. Calcd. for C24H34N402. 0.251H20 C, 70.21; H, 8.35; N, 13.65.

3 0 Found: C, 69.44; H, 8.38; N, 13.50%.

NMR (300 MHz, CD3OD) 850.95-2.83 (in, 19H), 2.08 (mn, 211), 3.41 (in, 411), 4.94 311), 5.09 1H), 7.29-7.63 (mn, 411).

WO 95/14676 PTU9134 PCT/US94/13544 19 EXAMPLE 14 (±)-3-(2,4-Dichlorophenyl)-N-[2,3-dihydro-1 (hexahydroazepin-l-yl)-1H-1 .4-benzodiazepin-3-yllprop~anamide m.p. 155-157'C.

Anal. Calcd. for C25H28C 12N402.HC1, 0. 12 EtOAc: C, 57.26; H, 5.65; N, 10.48.

Found: C, 57.66; H, 5.75; N, 10.08%.

NMR 8: 8.66 J 9.0 Hz, 1H), 7.80-7.74 (in, 1H), 7.56-7.41 (mn, 3H), 7.32-7.23 (in, 2H), 7.14 (dd, J 8.3, 2.2 Hz, 1H), 5.68 (nm, 1H), 4.27- 4.00 (mn, 2H), 3.58-3.5 (mn, 2H), 3.46 3H), 3.07 J 7.6 Hz, 2H), 2.86-2.77 (in, 2H), 2.18-1.99 (Mn, 2H), 1.86-1.56 (in, 6H).

EXAMPLE (±)-3-cyclohexyl-N-[2,3-Dihydro-l1-methyl-2-oxo-5-(hexahydroazepin- 1 -vl)-1H1 .4-benzodiazepin-3-yllpropanamide in.p. 100-102'C.

Anal. Caled. for C25H36N402.HCl, 0.50 H20; 0.30 EtOAc: C, 63.38; H, 8.2; N, 11.28.

Found: C, 63.36; H, 8.09; N, 11.3%.

8: 8.54 J 9.0 Hz, 1H), 7.79-7.74 (in, 1H), 7.54 J 7.8 Hz, 1H), 7.49-7.40 (mn, 2H), 5.69 (dd, J 9.0, 5.6 Hz, 2H), 4.55-4.4 (in, 1H), 4.20-4.00 (it, 1H), 3.54-3.49 (in, 2H), 3.46 3H), 2.47-2.41 (in, 2H), 2.09-1.97 (mn, 5H1), 1.82-1.51 (mn, 10H), 1.28-1.12 (in, 41H), 0.93-0.85 3 0 (mn,2H).

WO 95/14676 WO 9514676PCTIIJS94/13544 20 EXAMPLE 16 (±)-N-[2,3-Dihydro-l1-methyl-2-oxo-5-(hexahydroazepin-1 -yl)-l11-1,4benzodiazepin-3-yll -4-cyclohexylbutanamide m.p. 186.5-187.5'C.

Anal. Calcd. for C26H38N402: C, 71.2; H, 8.73; N, 12.77.

Found: C, 70.15; H, 8.45; N, 12.32%.

8H(CD3OD): 0.90 (in, 2H), 1.23 (in, 8H), 1.42-1.88 (in, 13H), 3.38 (mn, 7H), 5.10 1H), 7.31-7.63 (in, 4H).

EXAMPLE 17 [2,3-Dihydro-l1-inethyl-2-oxo-5-(hexahydroazepin- l-yI)- IH- 1,4benzodiazepin-3-yll -5-p2henvip~entanamide in.p. 140-141'C.

8H(CD3OD) 1.66 (mn, 12H), 2.36 (in, 2H), 2.66 (mn, 2H), 3.38 (in, 711), 5.10 1H), 7.20-7.56 (mn, 911).

Anal. Calcd. for C27H34N402 with 0.25 water: C, 72.62; H, 7.67; N, 12.55.

Found: C, 71.88; H, 7.71; N, 12.42%.

EXAMPLE 18 [2,3-Dihydro-l1-methyl-2-oxo-5-(hexahydroazepin- l-yl)- 1H- 1,4benzodiazepin-3-yl] -3-[4-trifluoromethylp~henyll-1ropanamide m.p. 169-170'C.

Anal. Calcd. for C26H29N402F32: WO 95/14676 PTU9/34 PCT/US94/13544 21 C, 64.18; H, 6.01; N, 11.52.

Found: C, 63.01; H, 5.77; N, 11.21%.

8H(CD3OD) 1.60 (in, 8H), 2.65 (in, 2H), 2.99 2H), 3.39 (mn, 7H), 5.10 1H), 7.31-7.62 (in, FLt1).

By using N-methylbenzylamine in place of N-inethylcycloliexylamine, and the appropriate acid, the following compound was prepared using the processes substantially as described in Example 1.

EXAMPLE 19 (±+)-N-112,3-Dihydro-l1-methyl-2-oxo-5-(N-benzyl-N-inethylamino)- 1H- 1 .4-benzodiazepin-3-vll-3-[2.4-dichlorop~henvllpropanamide m.p. 169-170*C.

6H(DMSO) 0.80 (mn, 2H), 1.09 (mn, 7H), 1.36 (in, 5H), 1.62 (in, 2.16 2H), 2.78 6H), 4.40 (mn, 1H), 4.90 1H), 7.33 7.62 (in, 4H), 8.41 1H).

By using dimethylaniine in place of N-methylcyclohexylamine and the appropriate acid, the fullowing compound was prepared using the process substantially as described in Example 1.

EXAMPLE -Dihydro-l1-inethyl-2-oxo-5-(N,N-diinethylamino)- 1 H-i ,4benzodiazepin-3-vll -3 -cvclohexvlp~rop~anainide m.p. 197.5-198'C.

Anal. Calcd. for C21H30N402.0.05 mm I WO 95/14676 PTU9/34 PCT/US94/13544 22 C, 68.08; H, 8.16; N, 15.12.

Found: C, 67.91; H, 8.17; N, 14.95%.

NMR (300 MHz, CDC13) 8 0.81-1.77 (mn, 1H), 2.30 (mn, 2H), 2.86 (s, 6H), 3.21 3H), 5.26 1H), 6.99 11i1 7.22-7.52 (mn, 4H) 2,3-Dihydro- 1-benzyl-2-oxo-1H-1 ,4-benzodiazepine-2,5dione was prepared from N-benzylisatoic anhydride (Transworld Chemicals) and glycine using the method described by Bock et al., J.

Org. Chem. 52, 1644, (1987). This was then reacted with dimethylamine in place of the N-methylcyclohexylaniine, and the appropriate acid substantially as described above in Example 1 to give the following compounds: EXAMPLE 21 [2,3-Dihydro-l1-berizyl-2-oxo-5-(N,N-diinethylainino)-l11-1,4benzodiazep~in-3-yfl-3- r2,4-dichlorophenyll-propanamide in.p. 193-194'C.

Anal. Calcd. for C27H26Cl2N402: C, 63.66; H, 5.14; N, 11.

Found: C, 63.73; H, 5.11; N, 11.16%.

8iH(DMSO) 2.53 (mn, 211), 2.86 2H), (3.34, s) 6H], 4.80 (d, 1H), -5.05 (in, 1H), 5.49 1H), 6.94-7.72 (mn, 12H), 8.79 1H).

EXAMPLE 22 [2,3-Dihydro-l1-benzyl-2-oxo-5-(N,N-dimethylamino)- 1H- 1,4benzodiazepin- 3-vll- 3-cyclohexyiprop~anamide in.p. 136-137'C.

WO 95/14676 WO 95/4676 CT/US94/13544 23 Anal. Calcd. for C27H34N402: C, 72.62; H, 7.67; N, 12.55.

Found: C, 72.35; HI, 7.56; N, 12.62%.

8H(CD3OD) 0.84 1.82 (in, 13H1), 2.35 (in, 2H), 2.68 6H1), 4.74 (d, 1H1), 5.16 1H), 5.65 1H1), 7.04-7.67 (in, 9H).

2,3-Dihydro-1 -isopropyl-2-oxo- 1H-1 ,4-benzodiazepine- 2,5-dione was prepared from N-isopropylisatoic anhydride and glycine using the method described by Bock, et al., I Org. Chem. 52, 1644, (1987). This was then reacted with dimethylamine in place of the Nmethyl cyclohexylamine, and the appropriate acid substantially as described in Examnple 1 to give the following compounds: EXAMPLE 23 (±)-N-[2,3-dihydro-l1-isopropyl-2-oxo-5-(N,N-dimnethylarnino)- 1H-1 ,4benzodiazepin-3-vll -3-cyclohexylpropanamide in.p. 209-210'C.

Anal. Calcd. for C23H34N402 with .95 C, 66.45; H, 8.71; N, 13.48.

Found: C, 66.38; H, 8.23; N, 13.5%.

EXAMPLE 24 (±)-N-[2,3-Dihydro-l1-isopropyl-2-oxo-5-(N,N-diinethylaino)- IH-i ,4benzodiazep~in-3-yl -3 -[2,4-dichlorop~henyliprOpanainide m.p. 219-220'C.

Anal. Calcd. for C23H26CI2N402 0.9 H120:

I

WO 95/14676 PCTUS94113544 24 C, 57.84; H, 5.87; N, 11.73.

Found: C, 57.83; H, 5.50; N, 11.72%.

NNvR (300 MHz, DMSO) 8 1.09 311), 1.36 3H), 2.49 (in, 2H), 2.80 8H), 4.40 (in, 1H1), 4.90 1H1), 7.28-7.61 (in, 7H), 8.62 (d, 1H).

2,3-Dihydro-l1-phenyl-2-oxo- 1H- 1,4-benzodiazepin-2,5dione (Japanese Patent 21,617) was carried forward as described above using dimethylamnine in place of N-methylcyclohexylamine- wid the appropriate carboxylic acid to give the compounds of Examples 25 and 26.

EXAMPLE 3-Dihydro-l1-phenyl-2-oxo-5-(N,N-dimethylamino)- 1H- 1,4benzodi. zepin-3-yJ 1-2-cycILhexvlacetamide m.p. 264-266'C.

Anal. Calcd. for C25H30N402, C, 71.12; H, 7.26; N, 13.2'/.

Found: C, 71.12; H, 7.15; N, 13.29%.

NMR (300 MHz, DM4SO) 8: 8.57 J 8.1 Hz, 1H), 7.54 (dcl, J 7.8, 0.6 Hz, 1H), 7.1-7.5 (in, 711), 6.92 J 8.1 Hz, 1H), 5.15 J 7.6 Hz, 111), 2.88 6H), 2.07 J 6.8 Hz, 211), 0.8-1.8 (in, 1111).

EXAMPLE 26 (+)-N-[2,3--Dihydro-1 -phenyl-2-oxo-5-(.N,N-dimnethlylamnino)-l11-'1,4benzodiazepin..3-vll-3-(2.4-dichlorophenyl'propanamide in.p. 259-260'C.

WO 95/14676 WO 9514676PCTlUS94/13544 25 Anal. Calcd. for C26H24C12N402: C, 62.86; H, 4.81; N, 11.35.

Found: C, 63.04; H, 4.88; N, 11.31%.

NMR (300 Hz, DMSO) 5: 8.79 J 7.8 Hz, 1H), 7.1-7.6 (in, 7H1), 6.91 (dd, J 8.4, 0.9 Hz, 1H1), 5.17 J 7.8 Hz, 111), 2.9 611), 2.85 211), 2.55 211).

2,3-Dihydro-l1-propyl-2-oxo-l11-1 ,4-benzodiazepin-2,5dione, was carried forward as described above using dimethylamine or N-methylcyclohexylamine and the appropriate carboxylic acid to give the compounds of Examples 27-30.

EXAMPLE 27 (±)-N-[2,3-Dihydro-l1-propyl-2-oxo-5-(N-cyclohexvl-N-methylamino)- 1H- 1.4-benzo-diazepin-3-yll-3-cyclohexylpropionamide m.p. 144-145'C.

Anal. Calcd. for C28H42N402, 0.25 C, 71.37; H, 9.09; N, 11.89.A Found: C, 71.4; 11, 8.95; N, 11.82%.

NMR (300 M~z, DMSO) d: 8.43 J 7.8 Hz, 111), 7.25-7.6 (mn, 411), 4.92 J 8.1 Hz, 1H1), 4.2 (in, 111), 3.55 (in, 111), 2.64 311), 2.16 (brt, 211), 0.7-1.9 (in, 2511), 0.65 J 7.3 Hz, 311).

EXAMPLE 28 (±)-N-[2,3-Dihydro-l1-propyl-2-oxo-5-(N-cyclohexyl-N-methylamino)- 111-1,4-benzo-diazepin-3-ylI-2-cvclohexvlacetainide WO 95/14676 WO 9514676PCTIUS94/13S44 26 m.p. 137-140'C.

Anal. Caled. for C27H40N402, 1.0 C, 68.9; H, 9; N, 11.9.

Found: C, 68.8; H, 8.93; N, 11.98%.

NMR (300 MHz, DMSO) 8: 8.43 J 7.8 Hz, 1H), 7.25-7.65 (in, 4H), 4.92 J 8 Hz, 1H), 4.22 (mn, 1H), 3.58 (in, 1H), 2.65 3H), 0.8-2.15 (mn, 25H), 0.65 3H).

EXAMPLE 29 (±)-N-[2,3-Dihydro-1 1 H-I 4-benzo-diazepin-3-vl] -3-(2.4-dichlorophenyl)propionamide in.p. 167-169'C.

Anal. Calcd. for C28H34C12N402: C, 63.51; H, 6.47; N, 10.58.

Found: C, 63.44; H, 6.44; N, 10.46%.

NMR (300 MHz, DMSO) 8: 8.66 J 8.3 Hz, 1H), 7.2-7-65 (in, 7H), 4.93 J 8.1 Hz, 1H), 4.20 (mn, 1H), 3.60 (in, 1H), 2.8 J 7.3 Hz, 2H), 2.64 3H), 2.5 2H), 0.8-1.9 (mn, 12H), 0.65 J 7.3 Hz, 3H).

EXAMPLE (±)-N-[2,3-Dihydro-1 -propy.l-2-oxo-5-(N,N-dimethylamino)-lH- 1,4benzodiazepin-3-vyl]-2-cyclohexylacetamide in.p. 196-197'C.

Anal. Calcd. for C22H32N402: WO 95/14676 PTU9134 PCT[US94/13544 27 C, 68.72; H, 8.39; N, 14.57.

Found: C, 68.54; H, 8.31; N, 14.44%.

NMR (300 MlHz, DMSO) 8: 0.59-2.12 (in, 16H), 2.78 (in, 2H), 3.32 6H), 3.58 (in, 1H), 4.19 (mn, 1H), 4.95 1H), 7.30-7.62 (mn, 4H), 8.46 1H).

Claims

1. A compound of structural formula: R 4 I N R 2 R 3 individual diastereomers, enantiomers and mixtures thereof or a pharmaceutically acceptable salt thereof wherein: X is Ci-4 alkylene, either straight or branched chain. R1 is 1) phenyl either unsubstituted or substituted with one or two substituents selected from chloro, bromo, iodo, fluoro, trifluoromethyl C1-3 alkoxy or nitro; 2) naphthyl, or 3) C5-7 cycloalkyl, R 2 and R 3 are independently 1) C1-3 alkyl, either straight or branched chain, and either unsubstituted or substituted with phenyl, or 2) C3-7 cycloalkyl; or R 2 and R 3 taken together represent a C4-7 methylene chain to form with the nitrogen to which they are attached a 5-8 membered azacycle; R 4 is 1) C1-4 alkyl, 2) phenyl or 3) benzyl; and R 5 is 1) hydrogen or r- WO 95/14676 PCT/US94/13544 29 2) C1-3 alkyl.

2. The compound of Claim 1, wherein R 2 and R 3 are joined together to form with the nitrogen to which they are attached a

5-8 membered azacycle. 3. The compound of Claim 2 selected from the group consisting of these depicted in the following table: R 4 N -N X-R1 N H N R 2 R 3 X R 1 R 2 R R4 -CH2- 1-naphthyl -(CH2)5- n-propyl -(CH2)2- 2,4-diCIPh -(CH2)6- methyl -(CH2)2- 4-CF3Ph -(CH2)6- methyl -(CH2)3- cyclohexyl -(CH2)6- methyl -(CH2)4- Ph -(CH2)6- methyl -CH2- 1-naphthyl -(CH2)6- n-propyl -(CH2)3- Ph -(CH2)6- methyl -(CH2)2- cyclohexyl -(CH2)6- methyl -CH2- cyclohexyl -(CH2)6- methyl 4. The compound of Claim 1, wherein R 2 and R 3 are independently C1-3 alkyl or C5-7 cycloalkyl. The compound of Claim 4 selected from the group consisting of those depicted in the following table: I WO 95/14676 WO 9514676PCT1US94/13544 30 N 0 0 N CH 3 X R! R -(CH2)2- 4-CF3Ph -CH3 -(CH2)3- cyclohexyl -CH3 -(CH2)2- 2,4-diCIPh -CH3 -(CH2)2- 2,4-diCiPh n-propyl -(CH2)2- cyclohexyl, n-propyl -CH2- cyclohexyl n-propyl -(CH2)2- Ph -CH3 -CH2- cyclohexyl -CH3 -(CH2)3- Ph -CH3 -(CH2)2- cyclohexyl -CH3

6. The compound of Claim 1 wherein R 2 and R 3 are independently C1-3 alkyl or C1-3 alkyl substituted with phenyl.

7. The compound of Claim 6 selected from the group consisting of those depicted in the following table: x -(CH 2 2 -(CH 2 2 -(CH 2 2 -(CH 2 2 -CH 2 -(CH 2 2 -(CH 2 2 -(CH2) 2 -(CH2)4- -(CH2)2- -CH 2 -CH 2 -(CH 2 2 -(CH 2 2 Ril 2,4-diCIPh 2,4-diCIPh cyclohexyl 2,4-diCIPh cyclohexyl 2,4-diCIPh cyclohexyl cyclohexyl Ph cyclohexyl cyclohexyl cyclohexyl 2,4-diCIPh cyclohexyl R 2 -C 2 H 5 -CH3 -CH3 -CH 3 -CH 3 -CH 3 -CH 3 -C 2 H 5 -C 2 H 5 -CH 3 -C 2 H 5 -CH 3 -CH3 -CH 3 S.. a *o *.aa a. a a R_ R4 -C 2 H 5 -CH 3 -CH 3 benzyl -CH 3 benzyl -CH 3 -Ph -CH 3 -Ph benzyl -CH 3 -CH 3 i-propyl -C2H 5 -CH 3 -C 2 H 5 -CH 3 -CH 3 -CH 3 -C 2 H 5 -CH 3 -CH 3 n-C3H7 -CH 3 i-propyl -CH 3 Ph substantially as hereinbefore described with a pharmaceutically acceptable carrier and a

8. A 3-acylaminobenzodiazepine derivative, reference to any one of the Examples.

9. A pharmaceutical formulation comprising 5 therapeutically effective amount of the compound of any one of Claims 1 to 8 or a pharmaceutically acceptable salt thereof. The pharmaceutical formulation of Claim 9 comprising in addition another antiarrlythimic agent or other cardiovascular agent.

11. A method of preventing or treating arrhythmia which comprises the administration to a patient in need of such treatment of an antiarrhythmically effective amount of the compound of any one of Claims 1 to 8, or the pharmaceutical formulation of Claim 9 or

12. The method of Claim 11 comprising the concomitant administration of another .eannt or other cardiovascular agent. Dated 21 June, 1996 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person -LV SPRUSON FERGUSON [n:\mer]00139:MER I INTERNATIONAL SEARCH REPORT In *tonal application No. PCT/US94113544 A. CLASSIFICATION OF SUBJECT MATITER IPC(6) :CO7D, 243/24 US CL :540/509 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) U.S. :540/509; 541/211 Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) CAS ON-LINE STN C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim NO. A US, A, 3,344,136 (BELL et al.) 26 September 1967. 1-11 A US, A, 3,414,563 (GRIOT) 03 December 1968. 1-11 Further docmets arm listed in the continuation of Box C. See patent family annex. SpecWa- ouii of ciled dama: doAmita~afa doe gmwW of of dhe sat wk w am coaskered to be of pulrmala ,mkvmcs emikrdomm-e pubL61mi o or aftr the ioeimau Min date dom-im which inay thre daubw an prioity chW(s) or whic a ekted bo .embi"h &a puduiaui. dew of moib cimliam or Other spe-a r specifiel) dommm earg I* m are disciame, ue, exh~iam or ad* doiplithd pio to the hwudami flg da hrnhw dim I-e prort d cab W ie namr,tpWAMW~ sir .w 6wmi MWn 4W pn-Wy dnm .Asllkwih the qip6iraliamhnciWe So mdwothe p, kipk .1v i vadwyWa tho uvam X doarmm of pusaumkr relevmca the ekabins wv ua. be ceasidwud maormrAst e emidemdoo o lve my mvW q wham tho dom it Wk slaow a= of pfalkbr efoleinedie Aimed hrvmm cam be wm so wivv m biv~v &V whn ase do-a~ is casabbe with ams aor m other m& doa. mch oabWWar bob ab~am toa spsmi shAW in the wt m P-0~dt h amly Date of the actual completion of the international search 21 FEBRUARY 1995 I D7at f gfthe interiationalaearch report 24 MARJU Name and mailing address of the ISAILJS Commissioner of Palents and Trademarks Box PaI Wakbnio, D.C. 20231 Facsimile No. (703) 305-3230 Form PCTflSA/210 (second shet)(uly 1992)*